The present invention includes novel heteroaryl or heterocyclic 1,3-bis-(substituted-phenyl)-2-propen-1-ones as well as methods and compositions for the treatment of disorders mediated by VCAM-1 or MCP-1 and for the treatment of inflammatory disorders generally that include the administration of a 1,3-bis-(substituted-phenyl)-2-propen-1-one that has at least one phenyl substituent that is an aryl, heteroaryl or heterocyclic moiety.
Adhesion of leukocytes to the endothelium represents a fundamental, early event in a wide variety of inflammatory conditions, autoimmune disorders and bacterial and viral infections. Leukocyte recruitment to endothelium is mediated in part by the inducible expression of adhesion molecules on the surface of endothelial cells that interact with counterreceptors on immune cells. Endothelial cells determine which types of leukocytes are recruited by selectively expressing specific adhesion molecules, such as vascular cell adhesion molecule-1 (VCAM-1), intercellular adhesion molecule-1 (ICAM-1), and E-selectin. VCAM-1 binds to the integrin VLA-4 expressed on lymphocytes, monocytes, macrophages, eosinophils, and basophils but not neutrophils. This interaction facilitates the firm adhesion of these leukocytes to the endothelium. VCAM-1 is an inducible gene that is not expressed, or expressed at very low levels, in normal tissues. VCAM-1 is upregulated in a number of inflammatory diseases, including arthritis, asthma, dermatitis, psoriasis, cystic fibrosis, post transplantation late and chronic solid organ rejection, multiple sclerosis, systemic lupus erythematosis, inflammatory bowel diseases, autoimmune diabetes, diabetic retinopathy, rhinitis, ischemia-reperfusion injury, post-angioplasty restenosis, chronic obstructive pulmonary disease (COPD), glomerulonephritis, Graves disease, gastrointestinal allergies, conjunctivitis, atherosclerosis, coronary artery disease, angina and small artery disease.
Coronary heart disease (CHD), primarily as a result of atherosclerosis, remains the leading cause of death in industrialized countries. Atherosclerosis is a disease characterized by vascular inflammation, deposition of lipids in the arterial vessel wall and smooth muscle cell proliferation resulting in a narrowing of the vessel passages. In advanced stages of the disease atherosclerotic lesions can become unstable resulting in plaque rupture, thrombosis, myocardial infarction and ischemic heart disease. It is now well accepted that the initiating events in atherosclerosis are local injury to the arterial endothelium that results in the induction of VCAM-1 and recruitment of mononuclear leukocytes that express the integrin counterreceptor, VLA-4, (O""Brien, et al., J. Clin. Invest., 92: 945-951, 1993). Subsequent conversion of leukocytes to foamy macrophages results in the synthesis of a wide variety of inflammatory cytokines, growth factors, and chemoattractants that help propagate formation of the mature atheromatous plaque by further inducing endothelial activation, leukocyte recruitment, smooth muscle cell proliferation, and extracellular matrix deposition. Pharmacological inhibition of VCAM-1 expression has been shown to inhibit atherosclerosis in several animal models (Sundell et al., Circulation, 100: 42, 1999). A monoclonal antibody against VCAM-1 has also been shown to inhibit neointimal formation in a mouse model of arterial wall injury (Oguchi, S., et al., Arterioscler. Thromb. Vasc. Biol., 20: 1729-1736, 2000).
Asthma, which is increasing in prevalence and morbidity world-wide, is a chronic inflammatory disease characterized by lung eosinophilia and bronchial hyperreactivity. The interaction between VCAM-1 on lung endothelial cells and VLA-4, which is the integrin counterreceptor expressed on eosinophils, is thought to be important for selective eosinophil recruitment. Eosinophils have been considered an important effector cell in the pathogenesis of asthma and other allergic diseases. Activated eosinophils release proteins such as major basic protein (MBP) that have been demonstrated to induce bronchial hyperreactivity, one of the defining criteria of asthma (Bousquot, et al., N. Engl. J. Med., 323: 1033-1039, 1990). It has been demonstrated that VCAM-1 is markedly upregulated on human bronchial vascular endothelium of subjects with asthma who have air flow limitation, when compared with subjects without asthma (Pilewski, et al., Am. J. Respir. Cell Mol. Biol., 12, 1-3,1995; Ohkawara, Y., et al., Am. J. Respir. Cell Mol. Biol., 12, 4-12, 1995; Gosset, P., et al., Int. Arch. Allergy Immunol. 106: 69-77, 1995; Hacken, N. H., et al., Clin. Exp. Allergy, 28 (12): 1518-1525, 1998). An elevation in serum soluble VCAM-1 levels has also been demonstrated in patients undergoing a bronchial asthma attack compared with levels under stable conditions (Montefort, S., Koizumi, A., Clin. Exp. Immunol., 101: 468-73, 1995). Several animal studies further demonstrate a spatial and temporal association between VCAM-1 and asthma. In a mouse model of allergic asthma, VCAM-1 expression was shown to be induced by allergen challenge, and administration of an anti-VCAM-1 antibody was effective in inhibiting eosinophil infiltration that occurred in this model (Metzger, W. J., et al., J. Allergy Clin. Immunol., 93: 183, 1994). Further evidence for the importance of VCAM-1 in allergic asthma comes from work in IL-12 knockout mice. IL-12 knockout mice had fewer eosinophils and VCAM-1 expression than wildtype mice; however, administration of recombinant IL-12 at the time of ova sensitization and challenge restored lung VCAM-1 expression and eosinophilia (Wang, S., et al., J. Immunol., 166:2741-2749, 2001). There are several examples where blocking the integrin receptors for VCAM-1 have had positive effects on animal models of asthma (Rabb et al., Am. J. Respir. Care Med. 149: 1186-1191, 1994; Abraham, W, et al., Am. J. Respir. Crit. Care Med. 156: 696-703. 1997) further demonstrating the importance of VCAM-1/VLA-4 interactions in allergic inflammation. Eosinophils are also important effector cells in allergic rhinitis. VCAM-1 has been demonstrated to be upregulated 24 hrs after nasal allergen provocation in patients with seasonal allergic rhinitis but not in normal subjects (Braunstahl, G. J., et al., J. Allergy Clin. Immunol., 107: 469-476, 2001).
Rheumatoid arthritis (RA) is a clinical syndrome of unknown cause characterized by symmetric, polyarticular inflammation of synovial-lined joints. The role of adhesion molecules in the pathogenesis of rheumatoid arthritis (RA) has also been well documented, and VCAM-1 expression on synovial fibroblasts is a clinical hallmark of RA (Li, P., et al., J. Immunol. 164: 5990-7, 2000). VLA-4/VCAM-1 interactions may be the predominant mechanism for recruitment of leukocytes to the synovium (Dinther-Janssen, et al., J. Immunol. 147: 4207-4210, 1991; Issekeutz and Issekeutz, Clin. Immunol. Immunopathol. 61:436-447, 1991; Morales-Ducret et al., J. Immunol. 149:1424-1431, 1992; Postigo et al., J. Clin. Invest. 89:1445-1452, 1992; Matsuyama, T., et al, Hum. Cell, 9: 187-192,1996). In support of this, increased VCAM-1 expression has been found in RA synovial tissue compared with osteoarthritis and control tissue (Wilkinson et al., Lab. Invest. 69:82-88, 1993; Furuzawa-Carballeda, J., et al., Scand. J. Immunol. 50: 215-222; 1999). Soluble VCAM-1 is higher in RA patients than in control subjects (Kolopp-Sarda, M. N., et al., Clin. Exp. Rheumatol. 19: 165-70, 2001). Soluble VCAM-1 has been shown to be chemotactic for T cells (Kitani, A., et al., J. Immun. 161: 4931-8, 1998), and in addition to being a possible diagnostic marker for RA, may contribute to its pathogenesis by inducing migration and recruitment of T cells. VCAM-1 expressed on fibroblast-like synoviocytes has also been implicated in enhanced survival of activated synovial fluid B cells (Marinova, Mutafcheia, L., Arthritis Rheum. 43: 638-644, 2000) that may further contribute to RA pathogenesis.
Chronic inflammation and accompanying vascular complications and organ damage characterize systemic lupus erythematosis (SLE). Recent studies suggest that VCAM-1 plays a role in SLE. Expression of VCAM-1 is increased on dermal vessel endothelial cells in patients with active systematic lupus erythematosus (Jones, S. M., British J. Dermatol. 135: 678-686, 1996) and correlates with increased disease severity (Belmont et al., Arthritis Rheum. 37:376-383, 1994). SLE muscle samples with perivascular infiltrate have greater endothelial cell expression of VCAM-1 compared with SLE patients without a perivascular infiltrate or with control samples (Pallis et al., Ann. Rheum. Dis. 52:667-671, 1993). Increased expression of VCAM-1 has also been demonstrated in kidneys of lupus-prone MRL/1 pr mice compared to nonautoimmune strains and its expression increased with disease severity (McHale, J. F., et al., J. Immunol. 163: 3993-4000, 1999). VCAM-1 expression on mesangial cells in vitro can be stimulated by IL-1, TNF-xcex1, and INFxcex3 exposure as well as by anti-endothelial cell IgG fraction and anti-DNA autoantibodies from SLE patients (Wuthrich, Kidney Int. 42: 903-914, 1992; Papa, N. D., et al., Lupus, 8: 423-429, 1999; Lai, K. N., et al., Clin Immunol Immunopathol, 81: 229-238, 1996). Furthermore, soluble VCAM-1 is higher in SLE patients than in normal subjects (Mrowka, C., et al., Clin. Nephrol. 43: 288-296, 1995; Baraczka, K., et al., Acta. Neurol. Scand. 99: 95-99, 1999; Kaplanski, G., et al., Arthritis Rheumol. 43: 55-64, 2000; Ikeda, Y., Lupus, 7: 347-354, 1998) and correlates with disease activity (Scudla, V., Vnitr. Lek., 43: 307-311, 1997).
Increased VCAM-1 expression has also been demonstrated in solid organ transplant rejection. Acute transplant rejection occurs when the transplant recipient recognizes the grafted organ as xe2x80x9cnon-selfxe2x80x9d and mounts an immune response characterized by massive infiltration of immune cells, edema, and hemorrage that result in the death of the transplanted organ. Acute rejection occurs in a matter of hours or days and has been correlated with increased levels of VCAM-1 in tissues and in plasma (Tanio et al., Circulation, 89:1760-1768, 1994; Cosimi et al., J. Immunol. 144: 4604-4612, 1990; Pelletier, R., et al., Transplantation, 55: 315, 1992). A monoclonal antibody to VCAM-1 has been shown to inhibit cardiac allograft rejection in mice (Pelletier, R., J. Immunol., 149: 2473-2481, 1992; Pelletier, R., et al., Transplantation Proceedings, 25: 839-841, 1993; Orosz, C. G., et al., J. Heart and Lung Transplantation, 16: 889-904, 1997) and when given for 20 days can cause complete inhibition of rejection and long-term graft acceptance (Orosz C. G., et al., Transplantation, 56: 453-460, 1993). Chronic graft rejection also known as allograft vasculopathy is distinct from acute transplant rejection and is a leading cause of late graft loss after renal and heart transplantation. Histologically it is characterized by concentric neointimal growth within vessels that is largely due to smooth muscle migration and proliferation. It is thought to be the result of endothelial damage brought about by several factors including: ischemia-reperfusion injury, immune complexes, hypertension, hyperlipidemia and viruses. All of these factors have been associated with induction of VCAM-1 in endothelial cells. There is also a strong correlation of soluble and tissue VCAM-1 levels with chronic rejection (Boratynska, M.,. Pol. Arch. Med. Wewn, 100: 410-410, 1998; Zembala, M., et al., Ann. Transplant. 2: 16-9, 1998; Solez K., et al., Kidney International., 51: 1476-1480, 1997; Koskinen P. K., et al., Circulation, 95: 191-6, 1997).
Multiple sclerosis is a common demyelinating disorder of the central nervous system, causing patches of sclerosis (plaques) in the brain and spinal cord. It occurs in young adults and has protean clinical manifestations. It is well documented that VCAM-1 is expressed on brain microvascular endothelial cells in active lesions of multiple sclerosis (Lee S. J., et al., J. Neuroimmunol., 98: 77-88, 1998). Experimental therapy of experimental autoimmune encephalomyelitis, which is an animal model for multiple sclerosis, using antibodies against several adhesion molecules, including VCAM-1, clearly shows that adhesion molecules are critical for the pathogenesis of the disease (Benveniste et al., J. Neuroimmunol. 98:77-88, 1999). A time and dose dependent expression of VCAM-1 and release of soluble VCAM-1 were detected in cultures of human cerebral endothelial cells induced by TNFxcex1, but not in peripheral blood mononuclear cells (Kallnann et al., Brain, 123:687-697, 2000). Clinical data also show that adhesion molecules in blood and cerebrospinal fluid are up-regulated throughout the clinical spectrum of multiple sclerosis (Baraczka, K., et al., Acta. Neurol. Scand. 99: 95-99, 1999; Reickmann, P., et al., Mult. Scler., 4: 178-182, 1998; Frigerio, S., et al., J. Neuroimmunol., 87: 88-93, 1998) supporting the notion that therapies which interfere with cell adhesion molecules such as VCAM-1 may be beneficial in modifying this disease (Elovaara et al., Arch. Neurol. 57:546-551, 2000).
Diabetes mellitus is a metabolic disease in which carbohydrate utilization is reduced and that of lipid and protein is enhanced. Evidence has accumulated that increased levels of adhesion molecules may play a functional pathophysiological role in diabetes (Wagner and Jilma, Hormone and Metabolic Research, 29: 627-630, 1997; Kado, S., Diabetes Res. Clin. Pract., 46: 143-8, 1999). It is caused by an absolute or relative deficiency of insulin and is characterized by chronic hyperglycemia, glycosuria, water and electrolyte loss, ketoacidosis, and coma. Elevated circulating adhesion molecules including VCAM-1 have been detected in patients with diabetes and in experimental models of diabetes in animals (Lorini et al., Hormone Research, 48: 153, 1997; Otsuki et al., Diabetologia, 40: A440, 1997; Hart et al., FASEB J. 11:A340, 1997; Albertini et al., Diabetologia, 39: A240, 1996; Wagner et al., Diabetologia, 39: A205, 1996; Enghofer et al., Diabetologia, 39: A97, 1996; Koga M., Diabet. Med., 15: 661-667, 1998). In addition, complications of diabetes often include peripheral vasculopathies such as diabetic retinopathy and diabetic nephropathy. It is believed that adhesion of leukocytes to the peripheral vasculature plays a central role in the vasculopathies often associated with diabetes.
Crohn""s disease, also known as regional enteritis, is a subacute chronic inflammatory condition of unknown cause, involving the internal ileum and less frequently other parts of the gastrointestinal tract. It is characterized by patchy deep ulcers that may cause fistulas, and narrowing and thickening of the bowel by fibrosis and lymphocytic infiltration. Ulcerative colitis is a chronic disease of unknown cause characterized by ulceration of the colon and rectum, with rectal bleeding, mucosal crypt abscesses, inflammatory pseudopolyps, abdominal pain, and diarrhea. It has been reported that serum VCAM-1 reflects the grade of intestinal inflammation in patients with Crohn""s disease or ulcerative colitis (Jones, et al., Gut, 36: 724-30, 1995; Goggins et al., Gastroenterology, 108: A825, 1995; Goeke and Manns, Gastroenterology, 106: A689, 1994; Goeke et al., J. Gasterokenterol. 32:480-486, 1997; Loftus et al., Gastroenterology, 108: A684, 1995; Tahami et al., Gastroenterology, 118: A344, 2000). Antibodies to VCAM-1 have been shown to ameliorate experimentally-induced colitis in mice (Soriano, A., Lab. Invest. 80: 1541-1551, 2000).
Psoriasis is a chronic skin disease characterized by erythematous scaling plaques as a result of keratinocyte hyperplasia, influx of immune cells and endothelial activation (Nickoloff, B. J., et al., J. Invest. Dermatol., 127: 871-884, 1991). VCAM-1 is upregulated in psoriatic skin as compared to normal skin (Groves, R. W., J. Am. Acad. Dermatol., 29: 67-72, 1993; Uyemura, K., et al., J. Invest. Dermatol. 101: 701-705, 1993) and levels of circulating VCAM-1 correlate with disease activity (Schopf, R. E., Br. J. Dermatol., 128: 34-7, 1993).
U.S. Pat. Nos. 5,750,351; 5,807,884; 5,811,449; 5,846,959; 5,773,231, and 5,773,209 to Medford, et al., as well as the corresponding WO95/30415 to Emory University indicate that polyunsaturated fatty acids (xe2x80x9cPUFAsxe2x80x9d) and their hydroperoxides (xe2x80x9cox-PUFAsxe2x80x9d), which are important components of oxidatively modified low density lipoprotein (LDL), induce the expression of VCAM-1, but not intracellular adhesion molecule-1 (ICAM-1) or E-selectin in human aortic endothelial cells, through a mechanism that is not mediated by cytokines or other noncytokine signals. This is a fundamental discovery of an important and previously unknown biological pathway in VCAM-1 mediated immune responses. As non-limiting examples, linoleic acid, linolenic acid, arachidonic acid, linoleyl hydroperoxide (13-HPODE) and arachidonic hydroperoxide (15-HPETE) induce cell-surface gene expression of VCAM-1 but not ICAM-1 or E-selectin. Saturated fatty acids (such as stearic acid) and monounsaturated fatty acids (such as oleic acid) do not induce the expression of VCAM-1, ICAM-1 or E-selectin.
PCT WO 98/51662, filed by AtheroGenics, Inc. and listing as inventors Russell M. Medford, Patricia K. Somers, Lee K. Hoong, and Charles Q. Meng, claims priority to provisional application U.S. Ser. No. 60/047,020, filed on May 14, 1997. This application discloses the use of a broad group of compounds as cardiovascular protectants that exhibit at least one, and sometimes a composite profile, of reducing cholesterol, lowering LDL, and inhibiting the expression of VCAM-1.
U.S. Pat. No. 5,155,250 to Parker, et al. discloses that 2,6-dialkyl-4-silylphenols are antiatherosclerotic agents. The same compounds are disclosed as serum cholesterol lowering agents in PCT Publication No. WO 95/15760, published on Jun. 15, 1995. U.S. Pat. No. 5,608,095 to Parker, et al. discloses that alkylated-4-silyl-phenols inhibit the peroxidation of LDL, lower plasma cholesterol, and inhibit the expression of VCAM-1, and thus are useful in the treatment of atherosclerosis.
PCT WO 98/51289, which claims priority to provisional application U.S. Ser. No. 60/047,020, filed on May 14, 1997 by Emory University listing Patty Somers as sole inventor, discloses the use of a group of compounds as cardiovascular protectants and antiinflammatory agents which exhibit at least one, and sometimes a composite profile, of reducing cholesterol, lowering LDL, and inhibiting the expression of VCAM-1 and thus can be used as antiinflammatory and cardivascular treat agents.
U.S. Pat. Nos. 5,380,747; 5,792,787; 5,783,596; 5,750,351; 5,821,260; 5,807,884; 5,811,449; 5,846,959; 5,877,203; and 5,773,209 to Medford, et al., teach the use of dithiocarbamates of the general formula A-SC(S)-B for the treatment of cardiovascular and other inflammatory diseases. Examples include sodium pyrrolidine-N-carbodithioate, tri-sodium N,N-di(carboxymethyl)-N-carbodithioate, and sodium N,N-diethyl-N-carbodithioate. The patents teach that the compounds inhibit the expression of VCAM-1.
PCT WO 98/23581 discloses the use of benzamidoaldehydes and their use as cysteine protease inhibitors.
PCT WO 97/12613 of Cornicelli et al. discloses compounds for the inhibition of 15-lipogenase to treat and prevent inflammation or atherosclerosis. Compounds disclosed include benzopyranoindole, benzimidazole, catacholes, benzoxadiazines, benzo[a]phenothiazine, or related compounds thereof.
Japanese Patent No. 06092950 to Masahiko et al. discloses preparation of epoxy compounds wherein electron deficient olefins such as acylstyrene derivatives, styrene derivatives, and cyclohexenone derivatives are efficiently oxidized by a hydrogen peroxide derivative in the presence of a primary or secondary amine in an organic solvent to give said epoxides which are useful intermediates for pharmaceutical and flavoring materials.
U.S. Pat. No. 5,217,999 to Levitzki et al. discloses substituted styrene compound as a method of inhibiting cell proliferation.
Chalcone (1,3-bis-aromatic-prop-2-en-1-ones) compounds are natural products related to flavonoids. PCT WO 99/00114 (PCT/DK98/00283) discloses the use of certain chalcones, 1,3-bis-aromatic-propan-1-ones (dihydrochalcones), and 1,3-bisaromatic-prop-2-yn-1-ones for the preparation of pharmaceutical compositions for the treatment of prophylaxis of a number of serious diseases including i) conditions relating to harmful effects of inflammatory cytokines, ii) conditions involving infection by Helicobacter species, iii) conditions involving infections by viruses, iv) neoplastic disorders, and v) conditions cause by microorganisms or parasites.
PCT WO 00/47554 filed by Cor Therapeutics describes a broad class of substituted unsaturated compounds for use as antithrombotic agents.
PCT 96/20936 (PCT/KR95/00183) discloses thiazolidin-4-one derivatives of the formula: 
which act as PAF antagonists or 5-lipoxygenase inhibitors. The compounds are used in the prevention and treatment of inflammatory and allergic disorders mediated by platelet-activating factor and/or leukotrienes.
U.S. Pat. No. 4,085,135 discloses 2xe2x80x2-(carboxymethoxy)-chalcones with antigastric and antiduodenal ulcer activities.
U.S. Pat. No. 5,744,614 to Merkle et al. discloses a process for preparing 3,5-diarylpyrazoles and various derivatives thereof by reacting hydrazine hydrate with 1,3-diarylpropenone in the presence of sulfuric acid and an iodine compound.
U.S. Pat. No. 5,951,541 to Wehlage et al. discloses the use of salts of aromatic hydroxy compounds, such as (hydroxyaryl)alkenone salts, as brighteners in aqueous acidic electroplating baths. In addition the invention discloses that such compounds have a lower vapor pressure than the known brighteners, as a single substance and in the electroplating baths,in order to avoid losses of substance. They also have high water solubility properties.
Japanese Patent No. 07330814 to Shigeki et al. discloses benzylacetophenone compounds as photoinitiator compounds.
Japanese Patent No. 04217621 to Tomomi discloses siloxane chalcone derivatives in sunscreens.
U.S. Pat. No. 4,085,135 to Kyogoku et al. discloses a process for preparation of 2xe2x80x2-(carboxymethoxy)-chalcones having antigastric and anti duodenal activities with low toxicity and high absorptive ratio in the body. This patent suggests that the high absorptive ratio in the body is due to the 2xe2x80x2-carboxymethoxy group attached to the chalcone derivative.
U.S. Pat. No. 4,855,438 discloses the process for preparation of optically active 2-hydroxyethylazole derivatives which have fungicidal and plant growth-regulating action by reacting an xcex1-xcex2-unsaturated ketone which could include a chalcone or a chalcone derivative with an enantiomerically pure oxathiolane in the presence of a strongly basic organometallic compound and at temperatures ranging from xe2x88x9280 to 120xc2x0 C.
European Patent No 307762 assigned to Hofmann-La Roche discloses substituted phenyl chalcones.
E. Bakhite et al. in J. Chem. Tech. Biotech. 1992, 55, 157-161, have disclosed a process for the preparation of some phenyloxazole derivatives of chalcone by condensing 5-(p-acetylphenyl)-2-phenyloxazole with aromatic aldehydes.
Herencia, et al., in Synthesis and Anti-inflammatory Activity of Chalcone Derivatives, Bioorganic and Medicinal Chemistry Letters 8 (1998) 1169-1174, discloses certain chalcone derivatives with anti-inflammatory activity.
Hsieh, et al., Synthesis and Antiinflammatory Effect of Chalcones, J. Pharm. Pharmacol. 2000, 52; 163-171 describes that certain chalcones have potent antiinflammatory activity.
Zwaagstra, et al., Synthesis and Structure-Activity Relationships of Carboxylated Chalcones: A Novel Series of CysLT1 (LT4) Receptor Antagonists; J. Med. Chem., 1997, 40, 1075-1089 discloses that in a series of 2-,3-, and 4-(2-quinolinylmethoxy)- and 3- and 4-[2-(2-quinolinyl)ethenyl]-substituted, 2xe2x80x2, 3xe2x80x2, 4xe2x80x2, or 5xe2x80x2 carboxylated chalcones, certain compounds are CysLT1 receptor antagonists.
JP 63010720 to Nippon Kayaku Co., LTD discloses that chalcone derivatives of the following formula (wherein R1 and R2 are hydrogen or alkyl, and m and n are 0-3) are 5-lipoxygenase inhibitors and can be used in treating allergies. 
JP 06116206 to Morinaga Milk Industry Co. Ltd, Japan, discloses chalcones of the following structure as 5-lipoxygenase inhibitors, wherein R is acyl and R1-R5 are hydrogen, lower alkyl, lower alkoxy or halo, and specifically that in which R is acyl and R1-R5 are hydrogen. 
U.S. Pat. No. 6,046,212 to Kowa Co. Ltd. discloses heterocyclic ring-containing chalcones of the following formula as antiallergic agents, wherein A represents a substituted or unsubstituted phenyl group, a substituted or unsubstituted naphthyl group, or a group: 
in which X represents a hydrogen or halogen atom or a hydroxyl, lower alkyl or lower alkoxyl group and B represents xe2x80x94CHxe2x95x90CHxe2x80x94,xe2x80x94N(R6)xe2x80x94, R6 is a lower alkyl group or a lower alkoxyalkyl group, xe2x80x94Oxe2x80x94 or xe2x80x94Sxe2x80x94; W represents xe2x80x94CHxe2x95x90CHxe2x80x94 or xe2x80x94CH2Oxe2x80x94, and R1-5 is the same or different and each independently represent a hydrogen or halogen atom, a hydroxyl, a lower alkyl, lower alkoxyl, carboxyl, cyano, alkyloxycarbonyl or tetrazolyl group, a group xe2x80x94CONHR7 in which R7 represents a hydrogen atom or a lower alkyl group, or a group xe2x80x94O(CH2)n R8 in which R8 represents a carboxyl, alkyloxycarbonyl or tetrazolyl group and n is from 1 to 4, with the proviso that at least one of the groups R1-5 represents a carboxyl, cyano, alkyloxycarbonyl or tetrazolyl group, the group xe2x80x94CONHR7 or the group xe2x80x94O(CH2)nR8; or a salt or solvate thereof. 
Reported bioactivies of chalcones have been reviewed by Dimmock, et al., in Bioactivities of Chalcones, Current Medicinal Chemistry 1999, 6, 1125-1149.
Given that VCAM-1 is a mediator of chronic inflammatory disorders, it is a goal of the present work to identify new compounds, compositions and methods that can inhibit the expression of VCAM-1. A more general goal is to identify selective compounds and methods for suppressing the expression of redox sensitive genes or activating redox sensitive genes that are suppressed.
It is therefore an object of the present invention to provide new compounds for the treatment of disorders mediated by VCAM-1.
It is also an object to provide new pharmaceutical compositions for the treatment of diseases and disorders mediated by the expression of VCAM-1.
It is a further object of the invention to provide compounds and methods of treating disorders and diseases mediated by VCAM-1, including cardiovascular and inflammatory diseases.
It is another object of the invention to provide compounds, compositions and methods to treat arthritis.
It is yet another object of the invention to provide compounds, compositions and methods to treat asthma.
It is another object of the invention to provide compounds, methods and compositions to inhibit the progression of atherosclerosis.
It is still another object of the invention to provide compounds, compositions, and methods to treat or prevent transplant rejection.
It is a further object of the present invention to provide compounds, methods and compositions for the treatment of lupus.
It is a further object of the present invention to provide compounds, methods and compositions for the treatment of inflammatory bowel disease.
It is a further object of the present invention to provide compounds, methods and compositions for the treatment of autoimmune diabetes.
It is a further object of the present invention to provide compounds, methods and compositions for the treatment of multiple sclerosis.
It is a further object of the present invention to provide compounds, methods and compositions for the treatment of diabetic retinopathy.
It is a further object of the present invention to provide compounds, methods and compositions for the treatment of rhinitis.
It is a further object of the present invention to provide compounds, methods and compositions for the treatment of ischemia-reperfusion injury.
It is a further object of the present invention to provide compounds, methods and compositions for the treatment of post-angioplasty restenosis.
It is a further object of the present invention to provide compounds, methods and compositions for the treatment of chronic obstructive pulmonary disease (COPD).
It is a further object of the present invention to provide compounds, methods and compositions for the treatment of glomerulonephritis.
It is a further object of the present invention to provide compounds, methods and compositions for the treatment of Graves disease.
It is a further object of the present invention to provide compounds, methods and compositions for the treatment of gastrointestinal allergies.
It is a further object of the present invention to provide compounds, methods and compositions for the treatment of conjunctivitis.
It is a further object of the present invention to provide compounds, methods and compositions for the treatment of dermatitis.
It is a further object of the present invention to provide compounds, methods and compositions for the treatment of psoriasis.
It has been discovered certain 1,3-bis-(substituted-phenyl)-2-propen-1-ones, including compounds of formula (I) inhibit the expression of VCAM-1, and thus can be used to treat a patient with a disorder mediated by VCAM-1. Examples of inflammatory disorders that are mediated by VCAM-1 include, but are not limited to arthritis, asthma, dermatitis, cystic fibrosis, post transplantation late and chronic solid organ rejection, multiple sclerosis, systemic lupus erythematosis, inflammatory bowel diseases, autoimmune diabetes, diabetic retinopathy, rhinitis, ischemia-reperfusion injury, post-angioplasty restenosis, chronic obstructive pulmonary disease (COPD), glomerulonephritis, Graves disease, gastrointestinal allergies, conjunctivitis, atherosclerosis, coronary artery disease, angina and small artery disease.
The compounds disclosed herein can also be used in the treatment of inflammatory skin diseases that are mediated by VCAM-1, as well as human endothelial disorders that are mediated by VCAM-1, which include, but are not limited to psoriasis, dermatitis, including eczematous dermatitis, Kaposi""s sarcoma, multiple sclerosis, as well as proliferative disorders of smooth muscle cells.
In yet another embodiment, the compounds disclosed herein can be selected to treat anti-inflammatory conditions that are mediated by mononuclear leucocytes.
In one embodiment, the compounds of the present invention are selected for the prevention or treatment of tissue or organ transplant rejection. Treatment and prevention of organ or tissue transplant rejection includes, but is not limited to treatment of recipients of heart, lung, combined heart-lung, liver, kidney, pancreatic, skin, spleen, small bowel, or comeal transplants. The compounds can also be used in the prevention or treatment of graft-versus-host disease, such as sometimes occurs following bone marrow transplantation.
In an alternative embodiment, the compounds described herein are useful in both the primary and adjunctive medical treatment of cardiovascular disease. The compounds are used in primary treatment of, for example, coronary disease states including atherosclerosis, post-angioplasty restenosis, coronary artery diseases and angina. The compounds can be administered to treat small vessel disease that is not treatable by surgery or angioplasty, or other vessel disease in which surgery is not an option. The compounds can also be used to stabilize patients prior to revascularization therapy.
In addition to inhibiting the expression of VCAM-1, the 1,3-bis-(substituted-phenyl)-2-propen-1-ones have the additional properties of inhibiting monocyte chemoattractant protein-1 (MCP-1) and smooth muscle proliferation. MCP-1 is a chemoattractant protein produced by endothelial cells, smooth muscle cells as well as macrophages. MCP-1 promotes integrin activation on endothelial cells thereby facilitating adhesion of leukocytes to VCAM-1, and MCP-1 is a chemoattractant for monocytes. MCP-1 has been shown to play a role in leukocyte recruitment in a number of chronic inflammatory diseases including atherosclerosis, rheumatoid arthritis, and asthma. Its expression is upregulated in these diseases and as such inhibition of MCP-1 expression represents a desirable property of anti-inflammatory therapeutics. Furthermore, smooth muscle cell hyperplasia and resulting tissue remodeling and decreased organ function is yet another characteristic of many chronic inflammatory diseases including atherosclerosis, chronic transplant rejection and asthma. Inhibition of the hyperproliferation of smooth muscle cells is another desirable property for therapeutic compounds.
In one embodiment, the invention provides a compound of the formula (I) 
or its pharmaceutically acceptable salt, wherein:
i) the wavy line indicates that the compound can be in the form of the E or Z isomer;
ii) R22 and R23 are independently hydrogen or (C1-C4)alkyl;
iii) R2xcex1, R3xcex1, R4xcex1, R5xcex1, R6xcex1, R2xcex2, R3xcex2, R4xcex2, R5xcex2 and R6xcex2 are independently
iv) hydrogen, alkyl, carbocycle, aryl, heteroaryl, heterocycle, cycloalkyl, alkoxy, aryloxy, arylalkoxy, heteroaryloxy, heteroarylalkoxy, alkylthio, alkyiamino, aminoalkyl, haloalkylthio, acyl, haloalkyl, aryloxy, amido, acylamino, amino, dialkylamino, aminodialkyl, trifluoroalkoxy, alkylsulfonyl, haloalkylsulfonyl, aminocarbonyl, alkenyl, alkynyl, halogen, hydroxyl, thiol, cyano, nitro, sulfonic acid, sulfonate, sulfate, sulfinic acid, sulfenic acid, sulfamide, sulfonamide, sulfoxide, metal sulfinate, phosphate, phosphonate, metal phosphonate, phosphinate, alditol, carbohydrate, amino acid, OC(R1)2CO2H, SC(R1)2CO2H, NHCHR1CO2H, COxe2x80x94R2, CO2R1, polyoxyalkylene, polyol alkyl, oxyalkylamino, alkylcarbonylalkyl, lower alkyl S(O)-lower alkyl, lower alkyl-S(O)2-lower alkyl; hydroxyalkyl, aralkoxy, heteroaryl lower alkoxy, heterocyclo lower alkoxy, heteroaryloxy, heterocycleoxy, aralkyl lower thioalkyl, heteroaralkyl lower thioalkyl, heterocycloalkyl lower thioalkyl, heteroaryl lower alkyl, heterocyclo lower alkyl, heteroarylthio lower alkyl, arylthio lower alkyl, heterocyclothio lower alkyl, heteroarylamino lower alkyl, heterocycloamino lower alkyl, arylsulfinyl lower alkyl, arylsulfonyl lower alkyl, any of which can be optionally substituted with a moiety that does not adversely affect the biological properties of the molecule; xe2x80x94C(O)(CH2)2CO2xe2x88x92M+, xe2x80x94SO3M+, or -lower alkyl-Oxe2x80x94R, wherein R is PO2(OH)xe2x88x92M+, PO3(OH)xe2x88x92M+ or xe2x80x94SO3M+, wherein M+ is a pharmaceutically acceptable cation; -lower alkylcarbonyl-lower alkyl; carboxy lower alkyl; -lower alkylamino-lower alkyl; N,N-di-substituted amino lower alkyl-, wherein the substituents each independently represent lower alkyl;
v) R1 is H, lower alkyl, an optionally substituted carbocycle, aryl, heteroaryl, heterocycle, alkylaryl, alkylheteroaryl, alkylheteroaryl or alkylheterocycle;
vi) R2 is an optionally substituted alkyl, alkenyl, alkynyl, aryl, carbocycle, heteroaryl, heterocycle, alkylaryl, alkylheteroaryl, alkylheteroaryl or alkylheterocycle;
vii) alternatively, R22 and R6xcex1 or R23 and R6xcex1, can join together to form a bridged carbocycle, aryl, heterocycle or heteroaromatic;
viii) R2xcex1 and R3xcex1, R3xcex1 and R4xcex1, R4xcex1 and R5xcex1, R5xcex1 and R6xcex1, R2xcex2 and R3xcex2, R3xcex2 and R4xcex2, R4xcex2 and R5xcex2 or R5xcex2 and R6xcex2 can independently join to form a bridged compound selected from the group consisting of an optionally substituted carbocycle, an optionally substituted cycloalkenyl, an optionally substituted cycloalkylcarbonyl, an optionally substituted cycloalkenylcarbonyl; an optionally substituted aryl, an optionally substituted heterocylic or an optionally substituted heteroaromatic, or alkylenedioxy or wherein the ring can include a carbonyl, cyclic ester, amide, amine, sulfonate, or phosphonate;
ix) at least one of R2xcex1, R3xcex1, R4xcex1, R5xcex1, R6xcex1, R2xcex2, R3xcex2, R4xcex2, R5xcex2 or R6xcex2 is, or R2xcex1 and R3xcex1, R3xcex1 and R4xcex1, R4xcex1 and R5xcex1, R5xcex1 and R6xcex1, R2xcex2 and R3xcex2, R3xcex2 and R4xcex2, R4xcex2 and R5xcex2 or R5xcex2 and R6xcex2 join together to be, an aryl, heterocycle or heteroaromatic; and
x) at least one of R2xcex1, R3xcex1, R4xcex1, R5xcex1, or R6xcex1, and at least one of R2xcex2, R3xcex2, R4xcex2, R5xcex2 or R6xcex2 is a substituent other than hydrogen.
In another embodiment, the compound is of the formula (II): 
or its pharmaceutically acceptable salt.
In another embodiment, R1 is independently H or lower alkyl, R2 is an optionally substituted alkyl; and at least one of R2xcex1, R3xcex1, R4xcex1, R5xcex1, or R6xcex1, and at least one of R2xcex2, R3xcex2, R4xcex2, R5xcex2 or R6xcex2 is a substituent other than hydrogen.
In another embodiment, R4xcex2 or R5xcex2 is optionally substituted heteroaryl or heterocycle; and at least one of R2xcex1, R3xcex1, R4xcex1, R5xcex1, or R6xcex1 is a substituent other than hydrogen.
In another embodiment, R4xcex1 or R5xcex1 is optionally substituted heteroaryl or heterocycle; and at least one of R2xcex2, R3xcex2, R4xcex2, R5xcex2, or R6xcex2 is a substituent other than hydrogen.
In a particular embodiment, R5xcex2 is optionally substituted thienyl or benzothienyl; R2xcex1, R3xcex1, R4xcex1, R5xcex1, R6xcex1, or R2xcex2, R3xcex2, R4xcex2, and R6xcex2 are independently hydrogen, methoxy, ethoxy propoxy, benzyloxy, 4-carboxybenzyloxy, 4-ethoxycarbonylbenzyloxy, 4-aminobenzyloxy, fluoro, chloro, bromo, iodo, hydroxy, OCH2CO2H, SCH2CO2H, NHCH2CO2H, CO2H, pyrid-2-ylmethoxy, pyrid-3-ylmethoxy, pyrid-4-ylmethoxy; thien-2-ylmethoxy, thien-3-ylmethoxy, fur-2-ylmethoxy, fur-3-ylmethoxy and at least one of R2xcex1, R3xcex1, R4xcex1, R5xcex1, or R6xcex1 is a substituent other than hydrogen.
In another embodiment, at least one of R2xcex1, R3xcex1, R4xcex1, R5xcex1, R6xcex1, R2xcex2, R3xcex2, R4xcex2, R5xcex2 or R6xcex2, is or R2xcex1 and R3xcex1, R3xcex1 and R4xcex1, R4xcex1 and R5xcex1, R5xcex1 and R6xcex1, R2xcex2 and R3xcex2, R3xcex2 and R4xcex2, R4xcex2 and R5xcex2 or R5xcex2 and R6xcex2 join to form a carbocycle, aryl, heterocycle or heteroaromatic in which the carbocycle, aryl, heteroaryl or heterocycle is a 5, 6 or 7 membered ring, optionally conjugated to another carbocycle, aryl, heteroaryl or heterocycle.
In one embodiment, the heteroaryl group is not an oxazole.
In yet another embodiment, either R3xcex1 and R4xcex1 or R5xcex1 and R4xcex1 join to form a 5-membered methylendioxyphenyl group.
In one alternative embodiment, one of the A or B rings has only hydrogen substituents.
While it has been known that certain chalcones exhibit antiinflammatory properties, it has not been reported that the presently disclosed class of 1,3-di-(substituted-phenyl)-2-propenones inhibit the expression of VCAM-1, and are useful anti-inflammatory agents.
One of the challenges of the prior biological use of chalcones has been that the phenyl groups of the chalcone can be metabolized by ring hydroxylation (by oxidizing enzymes, including but not limited to cytochrome P450) or via break down of the chalcone double bond. As part of the invention, the present chalcones include a heteroaryl, aryl or heterocyclic group attached to one of the phenyl rings to increase the half life and thus bioavailability of the compound. However, the addition of the heteroaryl, aryl or heterocyclic group can decrease the water solubility of the compound, which has the effect of actually limiting the bioavailability of the compound. Therefore, in a preferred embodiment, the chalcone contains both a heterocycle, heteroaromatic or aryl group on at least one of the A and B phenyl rings to limit the metabolism of the compound, and at least the group that increases the water solubility of the compound. Since phenyl hydroxylation typically occurs at the para position, in a preferred embodiment, the aryl, heteroaryl or heterocyclic group is positioned at the para position, or at a meta position that blocks para-hydroxylation. Alternatively, halogen, especially fluorine, increases metabolic stability when placed in the position(s) most susceptible to hydroxylation. Bulky alkoxy groups like cyclopropyl methoxy, heteroarylalkoxy (for example, thienyl methoxy, furryl methoxy and pyridyl methoxy) and heterocyclealkoxy also increase metabolic stability when placed at the meta or para position. It has been observed that adding the group that increases water solubility to the B ring typically increases the water solubility more than when the same group is added to the A ring, however, this trend may not hold true in all cases. Preferred water solubilizing groups are alkoxy, such as methoxy, OC(R1)2CO2H, SC(R1)2CO2H, NHC(R1)2CO2H or OC(R1)2CO2H, wherein R1 is H or lower alkyl. In a more general embodiment, any group that increases the water solubility of the compound can be used as substituents for R2xcex1, R3xcex1, R4xcex1, R5xcex1, R6xcex1, R2xcex2, R3xcex2, R4xcex2, R5xcex2 and R6xcex2, specifically including but not limited to
alkoxy, alkylthio, alkylamino, aminoalkyl, haloalkylthio, acyl, amido, acylamino, amino, dialkylamino, aminodialkyl, trifluoroalkoxy, alkylsulfonyl, haloalkylsulfonyl, aminocarbonyl, hydroxyl, thiol, cyano, nitro, sulfonic acid, sulfonate, sulfate, sulfinic acid, sulfenic acid, sulfamide, sulfonamide, sulfoxide, metal sulfinate, phosphate, phosphonate, metal phosphonate, phosphinate, alditol, carbohydrate, amino acid, COxe2x80x94R2, CO2xe2x80x94R2, polyoxyalkylene, polyol alkyl, NH2.HCl, oxyalkylamino, alkylcarbonylalkyl, lower alkyl S(O)-lower alkyl, lower alkyl-S(O)2-lower alkyl; imidazolyl lower alkyl, morpholinyl lower alkyl, thiazolinyl lower alkyl, piperidinyl lower alkyl, imidazolylcarbonyl, morpholinyl carbonyl, (lower alkyl)-aminocarbonyl, N-pyrrylpyridinyl-lower alkyl; pyridylthio-lower alkyl; morpholinyl-lower alkyl; hydroxyphenylthio-lower alkyl; cyanophenylthio-lower alkyl; imidazolylthio-lower alkyl; triazolylthio-lower alkyl; triazolylphenylthio-lower alkyl; tetrazolylthio-lower alkyl; tetrazolylphenylthio-lower alkyl; aminophenylthio-lower alkyl; N,N-di-substituted aminophenylthio-lower alkyl wherein the amine substituents each independently represent lower alkyl; amidinophenylthio-lower alkyl; phenylsulfinyl-lower alkyl; phenylsulfonyl lower alkyl;. -lower alkyl-Oxe2x80x94R, wherein R is PO2(OH)xe2x88x92M+ or PO3(OH)xe2x88x92M+ wherein M+ is a pharmaceutically acceptable cation; xe2x80x94C(O)(CH2)2CO2xe2x88x92M+; xe2x80x94SO3M+; -lower alkylcarbonyl-lower alkyl; -carboxy lower alkyl; -lower alkylamino-lower alkyl; N,N-di-substituted amino lower alkyl-, wherein the substituents each independently represent lower alkyl; pyridyl-lower alkyl; imidazolyl-lower alkyl; imidazolyl-Y-lower alkyl wherein Y is thio or amino; morpholinyl-lower alkyl; pyrrolidinyl-lower alkyl; thiazolinyl-lower alkyl; piperidinyl-lower alkyl; morpholinyl-lower hydroxyalkyl; N-pyrryl; piperazinyl-lower alkyl; N-substituted piperazinyl-lower alkyl, wherein the amine substituent is lower alkyl; triazolyl-lower alkyl; tetrazolyl-lower alkyl; tetrazolylamino-lower alkyl; or thiazolyl-lower alkyl; hydroxyalkyl, aralkoxy, heteroaryl lower alkoxy, heterocyclo lower alkoxy, heteroaryloxy, heterocycleoxy, aralkyl lower thioalkyl, heteroaralkyl lower thioalkyl, heterocycloalkyl lower thioalkyl, heteroaryl lower alkyl, heterocyclo lower alkyl, heteroarylthio lower alkyl, arylthio lower alkyl, heterocyclothio lower alkyl, heteroarylamino lower alkyl, heterocycloamino lower alkyl, arylsulfinyl lower alkyl, arylsulfonyl lower alkyl, any of which can be optionally substituted with a moiety that does not adversely affect the biological properties of the molecule;
In a preferred embodiment, after the target biological activity, metabolic stability and water solubility have been jointly optimized, substituent groups that do not contribute to these factors or contribute another attribute are removed.